Persons who have exceptionally high risk of developing cancer are studied to find explanations for their susceptibility. These unusual individuals are identified through referral by practitioners or self-referral, and through clinical observations at the bedside. With informed consent, epidemiologic inquiries are made to identify predisposing host and environmental factors, and concurrent laboratory studies help to clarify biologic mechanisms of cancer susceptibility. Results show that carriers of cancer genes develop cancer at very high rates in a few tissues. Early cancer detection has been achieved through screening of high-rish persons, and counseling has been provided to appropriate patients. High-risk patients also tend to develop multiple primary cancers in childhood, and nearly 1000 patients are under prospective observation for second cancers through the Registry of Survivors of Childhood Cancer in Boston.